Roles of peripheral and central opioid µ1-receptors in genesis of sudden death induced by intravenously bolus injection of fentanyl (FNT)

Intravenous (IV) rapid injection of overdose FNT could lead to sudden death, particularly in illicit users, which appears to occur more often in males than females. Although IV bolus (IVb) injection of FNT is able to produce an immediate long-lasting apnea via stimulation of vagal sensory afferents in anesthetized rats (Zhuang et al, JAP 2024), the mechanisms underlying the cardiorespiratory failure prior to sudden death in the conscious state are still not fully understood. This study sought to define: 1) a lethal dose of FNT (IVb) in conscious rats; 2) the impact of anesthesia on the lethal dose of FNT; and 3) the roles of peripheral and central opioid receptors (ORs), µ-ORs, and particularly µ1-ORs, in the genesis of death. The cardiorespiratory responses to IVb injection of 0.05, 0.2, 1-2, and 3 mg/kg FNT were recorded. The lethal dose-induced responses and mortality were compared between: conscious male and female rats; conscious and anesthetized states; and the rats pretreated without and with a given opioid antagonist. Naloxone (NLX) and naloxonazine (NLZ) were used to systemically antagonize ORs and µ1-ORs, and naloxone methiodide (NLM) and methylnaltrexone (MNTX) to peripherally block ORs and µ-ORs. In conscious rats, FNT at 0.05 and 0.2 mg/kg triggered an immediate sustained apnea and bradycardia followed by cardiorespiratory depression (bradypnea and bradycardia). The response to 0.05 mg/kg FNT was almost recovered 60 min postinjection and that to 0.2 mg/kg FNT recovered overnight. FNT at 3 but not 1-2 mg/kg resulted in sudden death without gender difference, which was featured by an immediate sustained apnea followed by a brief restoration of respiratory rhythm (for <1 min) and then respiratory and cardiac arrest at ~10 min postinjection. NLX generally blocked and NLZ substantially blunted the cardiorespiratory responses and both prevented death. NLM failed to prevent death (5/5) and MNTX prevented death in 3/8 rats. In addition, 0.05 mg/kg FNT caused death occurring within 5 min postinjection in anesthetized rats. In conclusion, IVb injection of FNT can induce sudden death, independent of gender, primarily via activation of central µ1-ORs presumably with limited involvement of peripheral µ1-ORs. In addition, the lethal dose of FNT is 60-fold lower in the anesthetized rats than in conscious ones. This study is supported National Institutes of Health (NIH), Bethesda. Grant numbers: HL163512 and DA059063. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.